This application is submitted in response to PAS-08-061 "Long-acting, sustainable therapies for opiate addiction". A heroin/morphine addiction treatment vaccine candidate has been developed which appears in preliminary studies to be highly effective in rats. The purpose of this proposal is to further characterize the immunogenicity, mechanism of action and efficacy of this vaccine in rats and mice and assess its readiness for clinical trials. Despite the availability of effective pharmacotherapies for treating heroin addiction, fewer than 1 in 5 opiate addicts in the U.S. choose to use these. Among the limitations of currently available medications are their relatively short duration of action, the need for tight regulation of dispensing, side effects or interference with the therapeutic use of other opiates, and the perception of "trading one addiction for another". New medications with mechanisms of action distinct from those already available could provide additional treatment options, and a long duration of action could increase their appeal and ease of use. Vaccines for nicotine and cocaine addictions are in clinical trials and preliminary data suggest efficacy. These vaccines reduce or slow the distribution of the target drug to brain, attenuating their effects. We (Anton lab) recently developed a highly immunogenic second-generation vaccine (morphine conjugated to tetanus toxoid;M-TT) directed against heroin and each of its active metabolites (6-MAM, morphine, morphine-6- gluc). Vaccination with M-TT elicits high concentrations of high affinity antibodies, and robustly blocks heroin or morphine self- administration in rats. We propose an integrated series of (Aim 1) immunologic, (Aim 2) pharmacokinetic, (Aim 3) behavioral and (Aim 4) safety studies to evaluate the clinical potential of this vaccine in rats and mice. Because heroin pharmacokinetics is complex, particular attention will be paid to characterizing and quantitating M-TT effects on heroin and each of its active metabolites. These data will allow us to understand how the binding of each of these moieties by antibody relates to vaccine efficacy, and will provide biomarkers that can be used to asses the adequacy of immunization in future clinical trials. The general hypotheses to be tested are that 1) M-TT immunogenicity can be further enhanced, and that M-TT remains immunogenic even in the presence of heroin, 2) M-TT acts through multiple complementary pharmacokinetic mechanisms involving heroin and each of its active metabolites, 3) M-TT attenuates heroin and morphine self-administration, and opiate-induced changes in brain reward thresholds over a range of clinically relevant opiate doses, and 4) M- TT is safe and does not itself precipitate opiate withdrawal. PUBLIC HEALTH RELEVANCE: There are an estimated 15 million opiate addicts worldwide and 1.2 million heroin addicts in the U.S. Heroin addiction is associated with disruption of crime, social disruption, and severe health consequences including the spread of HIV and hepatitis C. There are several medications already available or the treatment of heroin addiction, including methadone, buprenorphine and naltrexone. Although these have all been shown to be effective, fewer than 1 in 5 addicts in the U.S. choose to use them because of real or perceived drawbacks that result in low acceptability. The vast majority of heroin addicts are therefore not receiving treatment. Alternative medications, which could provide a greater choice of therapeutic options, might increase the number of addicts electing and staying in treatment. A non-addictive and long-acting medication which obviates the need for daily clinic visits would be of particular interest. Vaccines have been developed for the treatment of nicotine and cocaine addiction, and are in early clinical trials. These vaccines stimulate the production of antibodies that bind the drug and reduce the amount of drug reaching the brain, thereby reducing its addictive effects. Advantages of vaccines for addiction treatment are that they are safe, non-addictive, and have a very long duration of action (months) which can be extended as needed with additional booster doses. We have developed a heroin vaccine that stimulates production of high levels of antibodies and that can block some of the key addictive effects of heroin or morphine in rats. The proposed study will further characterize this vaccine, over a wide range of clinically relevant heroin doses, to assess whether it is suitable for advancement to clinical trials. The importance of this work is in providing an additional type of medication for those opiate addicts or abusers who find the currently available options unacceptable, or possibly for use in addition to existing medications to enhance their efficacy.